Sequential BCMA- and GPRC5D-targeted bispecific antibody therapy in multiple myeloma: Real-world outcomes and first report of dual bispecific antibody-refractory patients

Abstract

Abstract Introduction: BCMA and GPRC5D bispecific antibodies (BsAbs) are indispensable therapies for relapsed/refractory multiple myeloma (RRMM) often utilized sequentially, but there is a dearth of data describing the clinical course of patients receiving and progressing on sequential BsAbs. Furthermore, real-world dosing practices often deviate from the product label, but the impact on efficacy remains uncertain. We sought to characterize the real-world practice patterns and outcomes of patients receiving BCMA and GPRC5D BsAbs, including BCMA/GPRC5D BsAb dual refractory patients. Methods: We conducted a retrospective single-institution study evaluating RRMM patients treated with standard-of-care (SOC) teclistamab (tec) and/or talquetamab (tal) at UCSF between 2022 and 2025. Patient-, disease-, and treatment-related characteristics were collected and summarized descriptively. Patients previously exposed to BsAbs on a clinical trial, receiving tal as bridging therapy, or receiving tec/tal in combination with other agents were excluded. High-risk cytogenetics was defined as presence of del(17p), t(4;14), or t(14;16) on FISH. Multivariate analyses (MVA) of survival outcomes used Cox regression with the following covariates: use of alkylator, IMiD, or anti-CD38 antibody in the immediate prior line, history of transplant, extramedullary disease (EMD), cytogenetic risk, ISS stage III disease, baseline ferritin, absolute lymphocyte count (ALC), and C-reactive protein (CRP). Results: In total, 121 consecutive patients treated with SOC tec or tal monotherapy were included, with 95 receiving tec and 26 receiving tal as their first BsAb (BsAb1). Median age was 71 years, 59.5% were male, median prior lines of therapy was 5, 31.8% had high-risk cytogenetics, and 19.8% had EMD. With BsAb1, median 6-month relative dose intensity (total dose delivered/total dose intended per label over the first 6 mos) was 0.68. ORR with BsAb1 was 81.0% (75.2% VGPR+), median PFS (mPFS) was 17.1 mos and was similar between tec and tal (17.1 vs. 16.8 mos, respectively, p=0.61). EMD, high-risk cytogenetics, ISS stage III, and ferritin were associated with both shorter PFS and OS on univariate analysis and MVA (p<0.05). Use of anti-CD38 in the immediate prior line and higher ALC were associated with significantly longer PFS, and CRP with significantly shorter PFS on univariate analysis but not MVA (p=0.229, 0.464, 0.421, respectively). Among patients with prior BCMA CAR-T or ADC exposure (n=38), ORR with tal (n=16) was 87.5% (81.2% VGPR+), while ORR with tec (n=22) was 72.7% (72.7% VGPR+), p=0.27. mPFS with tal was longer than with tec (16.8 vs. 7.5 mos, p=0.24). Therapy with BsAb1 was discontinued early for a reason other than progressive disease in 34 patients (toxicity n=20, provider discretion n=14) after a median of 3.8 mos of therapy (IQR 2.1-10.1 mos). mPFS was not reached, 6-month PFS was 94%, and 12-month PFS was 82% in this cohort. After BsAb1, 22 patients received tec or tal as a second BsAb (BsAb2). ORR was 68.1% (54.5% VGPR+), median duration of response was 9.5 mos, and mPFS was 3.6 mos. Patients who attained VGPR+ with BsAb1 had higher rates of VGPR+ with BsAb2 than those who did not (71.4% vs. 25.0%, p=0.07). Time between last dose of BsAb1 and start of BsAb2 was not associated with ORR or PFS. Finally, 22 patients relapsed on both BCMA and GPRC5D BsAbs, with a median OS of 7.5 mos from the time of relapse on the latter BsAb. Among patients receiving a subsequent line of therapy (n=14), ORR was 42.9% mPFS was 3.5 mos. Conclusion: In this real-world analysis of tec and tal monotherapy, PFS with initial BsAb therapy exceeded that reported in clinical trials, despite lower relative dose intensity from early dosing interval extensions and finite treatment durations. Although ORRs remained high, PFS with a second BsAb was considerably shorter, even when changing targets. Importantly, to our knowledge, this is the first report to characterize outcomes in patients refractory to both BCMA- and GPRC5D-targeting BsAbs who have a dismal median OS of 7.5 months, highlighting a critical unmet need.